Administration of butyrate, beta-hydroxybutyrate, and related compounds in humans

ABSTRACT

In various implementations, beta-hydroxybutyrate, related compounds, and/or one or more other compounds may be administered to an individual to cause weight loss, weight maintenance, elevate blood ketone levels, maintain blood ketone levels, reduce blood glucose levels, maintain blood glucose levels, improve energy, focus, mood, cognitive function, or aide with neurological or inflammatory disorders and/or combinations thereof. Other compounds may include short chain fatty acids, short chain triglycerides, medium chain fatty acids, medium chain triglycerides, long chain fatty acids, long chain triglycerides, berberine, metabolites of berberine (e.g., dihydroberberine), and/or combinations thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 62/324,798, entitled “ADMINISTRATION OF BUTYRATE,BETA-HYDROXYBUTYRATE, AND RELATED COMPOUNDS IN HUMANS”, filed on Apr.19, 2016, which is incorporated by reference for all purposes.

TECHNICAL FIELD

The present invention relates to administration of butyrate,beta-hydroxybutyrate, and related compounds.

BACKGROUND

Currently, beta-hydroxybutyrate salts can be administered orally orintravenously in humans to promote weight loss and/or ketosis. However,the excess intake of salts such as sodium, magnesium, and potassium maybe unwarranted (e.g., high blood pressure, stroke, damage to organs,gastrointestinal problems, etc.). Thus, many people may not be able totolerate administration of beta-hydroxybutyrate salts in amounts topromote or sustain weight loss and/or ketosis. Polymers ofbeta-hydroxybutyrate have also been administered to humans to promoteketosis. However, since polymers must be processed by the body todeliver beta-hydroxybutyrate to the individual, the delivery is slowand/or a larger amount of the polymer must be administered to deliver aspecified amount of beta-hydroxybutyrate.

SUMMARY

In various implementations, a pharmaceutically effective amount ofbutyrate, beta-hydroxybutyrate, related compounds, and/or one or moreother compounds may be administered to an individual. For example, thepharmaceutically effective amount of the beta-hydroxybutyrate, relatedcompounds, and/or one or more other compounds may be administered tocause weight loss, weight maintenance, elevate blood ketone levels,maintain blood ketone levels, reduce blood glucose levels, maintainblood glucose levels, improve focus, energy, cognitive function,traumatic brain injury, diabetes, neurological disorders, cancer,inflammatory conditions, suppressing appetite, anti-aging,anti-glycation, epilepsy, depression, performance, strength, musclemass, fat loss, body composition, and/or use as a medicament etc. Thepharmaceutically effective amount of butyrate, beta-hydroxybutyrate,related compounds, and/or combinations thereof may be administered tohealthy individuals and/or not healthy individuals (e.g., with diseasesand/or disorders).

Implementations may include one or more of the following features. Thebeta-hydroxybutyrate may include the racemic mixture and/or theindividual isomers of beta-hydroxybutyrate, such asR-beta-hydroxybutyrate (also known as D-beta-hydroxybutyrate). Thebeta-hydroxybutyrate may include related compounds. Thebeta-hydroxybutyrate may be coupled to a compound such as an amino acid.The beta-hydroxybutyrate may include beta-hydroxybutyrate salt andbeta-hydroxybutyrate esters, in some implementations. Other compoundsmay include short chain fatty acids, short chain triglycerides, mediumchain fatty acids, medium chain triglycerides, long chain fatty acids,long chain triglycerides, berberine, berberine metabolites,dihydroberberine, tetrahydroberberine and/or combinations thereof. Oneor more of the other compounds may be unencapsulated and/orencapsulated.

In various implementations, a composition may be administered to induceand/or maintain ketosis. The composition may include approximately 0.5 gto approximately 10 g of R-beta-hydroxybutyrate.

Implementations may include one or more of the following features. Theamount of the composition administered may include approximately 0.5 toapproximately 3 g of R-beta-hydroxybutyrate. The composition may includeadditional composition, such as compositions that are capable ofindependently increasing ketone levels, inducing ketosis, and/ormaintaining ketosis. In some implementations, the composition mayinclude additional compositions to provide other health benefits (e.g.,increase mental acuity, strength, etc.). For example, the compositionmay include fatty acids and/or esters of fatty acids. For example, thecomposition may include a short chain fatty acid, an ester of shortchain fatty acid, a medium chain fatty acid, an ester of medium chainfatty acid, a long chain fatty acid, or an ester of long chain fattyacid. The composition may include flavoring(s), vitamin(s), mineral(s),and/or binder(s). The composition may be administered up to 5 timesdaily. The administration of the composition may increase strength,mental acuity, metabolism, fat loss, fat oxidation, motor function,muscle mass, and/or combinations thereof. In some implementations, the0.5 to 10 g of R-beta-hydroxybutyrate administered includesR-beta-hydroxybutyrate and at least one of a polymer ofR-beta-hydroxybutyrate or R-beta-hydroxybutyrate-complex.

In various implementations, a composition may include approximately 0.5g to approximately 10 g of R-beta-hydroxybutyrate and one or moreadditional compounds capable of maintaining ketosis independently.Administration of the composition may induce and/or maintains ketosis inan individual.

Implementations may include one or more of the following features. TheR-beta-hydroxybutyrate may include R-beta-hydroxybutyrate salt,R-beta-hydroxybutyrate-amino acid complex, and/or R-beta-hydroxybutyratepolymer. The additional compounds may include fatty acids and/or estersof fatty acids. The fatty acids and/or esters may include natural (e.g.,cream, coconut oil, macadamia oil, etc.) and/or artificial fatty acidsand/or esters of fatty acids. For example, the composition may include ashort chain fatty acid, an ester of short chain fatty acid, a mediumchain fatty acid, an ester of medium chain fatty acid, a long chainfatty acid, or an ester of long chain fatty acid. In someimplementations, additional compound(s) may include polymer(s) ofbeta-hydroxybutyrate, D,L-beta-hydroxybutyrate, butyrate, butyric acid,and/or triglyceride tributyrin. The additional compound(s) may includeberberine, dihydroberberine, and/or tetrahydroberberine.

In various implementations, pharmaceutically effective amounts ofR-beta-hydroxybutyrate and amino acid may be administered for inducingand/or maintaining ketosis.

Implementations may include one or more of the following features. Theamount of R-beta-hydroxybutyrate to induce and/or maintain ketosis in anindividual may be less than or equal to half of the amount ofD,L-beta-hydroxybutyrate to induce and/or maintain the same level ofketosis (e.g., as measured by blood ketone levels). In someimplementations, the amount of R-beta-hydroxybutyrate to induce and/ormaintain ketosis in an individual may be less than the amount ofD,L-beta-hydroxybutyrate or L-beta-hydroxybutyrate to induce and/ormaintain the same level of ketosis. The composition may includeapproximately 1 g to approximately 5 grams of R-beta-hydroxybutyrate andapproximately 0.5 to 2 g of amino acid. The amino acid may includeLeucine. The composition may include a mixture and/or complex of theR-beta-hydroxybutyrate and amino acid. At least a portion of theR-beta-hydroxybutyrate may be complexed with the amino acid, in someimplementations. For example, a portion of the R-beta-hydroxybutyratemay be administered in the composition as a salt and/or polymer andanother portion of the R-beta-hydroxybutyrate may be administered as acomplex with an amino acid (e.g., leucine). In some implementations, thecomposition may include at least one R-beta-hydroxybutyrate salt (e.g.,in additional to the pharmaceutically effective amounts ofR-beta-hydroxybutyrate in the composition and/or as the pharmaceuticallyeffective amounts of R-beta-hydroxybutyrate).

The details of one or more implementations are set forth in theaccompanying drawings and the description below. Other features,objects, and advantages of the implementations will be apparent from thedescription and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of this disclosure and its features,reference is now made to the following description, taken in conjunctionwith the accompanying drawings, in which:

FIG. 1 illustrates a table of blood ketone levels over time for 4subjects for an implementation of an example administration ofD,L-beta-hydroxybutyrate and RID-beta-hydroxybutyrate.

FIG. 2 illustrates a table of blood ketone levels over time for animplementation of an example administration of the microencapsulatedbutyrate compared to traditional sodium butyrate.

FIG. 3 illustrates a chart including lifespan of rats subject to animplementation of an administration of R-beta-hydroxybutyrate.

FIG. 4 illustrates a chart illustrating the results of motor skilltesting following an implementation of an example administrationprotocol.

FIG. 5A illustrates a chart illustrating fat loss results following animplementation of an example administration protocol.

FIG. 5B illustrates a chart illustrating fat mass and lean mass resultsfollowing an implementation of an example administration protocol.

FIG. 6 illustrates a chart illustrating LPL levels in rats following animplementation of an example administration protocol.

FIG. 7 illustrates a chart illustrating blood ketone levels following animplementation of an example administration protocol.

FIG. 8 illustrates a chart illustrating improvement over a placebofollowing an implementation of an example administration protocol.

FIG. 9 illustrates a chart illustrating perceived exertion following animplementation of an example administration protocol.

FIG. 10 illustrates a chart illustrating blood ketone levels followingan implementation of an example administration protocol.

FIG. 11 illustrates a chart illustrating blood ketone levels followingan implementation of an example administration protocol.

FIG. 12A illustrates a chart illustrating RER levels following animplementation of an example administration protocol.

FIG. 12B illustrates a chart illustrating RER levels following animplementation of an example administration protocol.

FIG. 13A illustrates a chart illustrating perceived hunger following animplementation of an example administration protocol.

FIG. 13B illustrates a chart illustrating perceived satiety following animplementation of an example administration protocol.

FIG. 13C illustrates a chart illustrating perceived energy following animplementation of an example administration protocol.

FIG. 14A illustrates a chart illustrating strength test resultsfollowing an implementation of an example administration protocol.

FIG. 14B illustrates a chart illustrating strength test resultsfollowing an implementation of an example administration protocol.

FIG. 14C illustrates a chart illustrating the results of the testing.

FIG. 15 illustrates a chart illustrating blood ketone levels followingan implementation of an example administration protocol.

FIG. 16 illustrates a chart illustrating blood ketone levels followingan implementation of an example administration protocol.

Like reference symbols in the various drawings indicate like elements.

DETAILED DESCRIPTION

In various implementations, compounds such as butyrate,beta-hydroxybutyrate and/or related compounds (e.g., derivatives,esters, polymers, etc.) can be administered alone or in combination withone or more other compounds. Administration of a pharmaceuticallyeffective amount of these compound(s) may promote and/or maintain weightloss and/or ketosis. In some implementations, blood ketone levels and/orblood glucose levels may be reduced and/or maintained within apredetermined range when a pharmaceutically effective amount of one ormore compounds are administered. In some implementations, a health of anindividual (e.g., strength, symptoms of disease, mental acuity, fastingglucose levels, etc.) may be improved and/or maintained byadministration of a compound that includes butyrate,beta-hydroxybutyrate and/or related compounds (e.g., derivatives,esters, polymers, etc.).

In various implementations butyrate, beta-hydroxybutyrate and/or relatedcompounds may be administered to a human. Beta-hydroxybutyrate (e.g.,R-beta-hydroxybutyrate, L-beta-hydroxybutyrate, and/orD,L-beta-hydroxybutyrate) may include beta-hydroxybutyrate salts and/orbeta-hydroxybutyrate esters. In some implementations,beta-hydroxybutyrate may include beta-hydroxybutyrate bound to anothercompound (e.g., amino acids) and/or polymers of beta-hydroxybutyrate.For example, beta-hydroxybutyrate (e.g., R-beta-hydroxybutyrate,L-beta-hydroxybutyrate, and/or D,L-beta-hydroxybutyrate) may includebeta-hydroxybutyrate salts, beta-hydroxybutyrate esters,beta-hydroxybutyrate sodium salt (e.g., sodium beta-hydroxybutyrate),beta-hydroxy butyrate potassium salt (e.g., potassiumbeta-hydroxybutyrate), beta-hydroxybutyrate calcium salt (e.g., calciumbeta-hydroxybutyrate), beta-hydroxybutyrate magnesium salt (e.g.,magnesium beta-hydroxybutyrate), beta-hydroxybutyrate lithium salt(e.g., lithium beta-hydroxybutyrate), sodium beta-hydroxybutyrate,arginine beta-hydroxybutyrate, lysine beta-hydroxybutyrate, histidinebeta-hydroxybutyrate, ornithine beta-hydroxybutyrate, creatinebeta-hydroxybutyrate, agmatine beta-hydroxybutyrate, or citrullinebeta-hydroxybutyrate, other appropriate organic salts that includebeta-hydroxybutyrate, and/or combinations thereof. In someimplementations, the beta-hydroxybutyrate may includebeta-hydroxybutyrate salts including (calcium, sodium, magnesium,potassium, zinc, selenium, chromium, other appropriate minerals, and/orcombinations thereof. In some implementations, the beta-hydroxybutyratemay be complexed and/or coupled to another compound (e.g., amino acidand/or berberine) and a beta-hydroxybutyrate salt may include a complex(e.g., chelate) that includes a mineral (e.g., calcium, zinc, etc.) andthe beta-hydroxybutyrate compound coupled to another compound. Thebeta-hydroxybutyrate may include single isomer beta-hydroxybutyrateand/or polymer beta-hydroxybutyrate. For example, R-beta-hydroxybutyratemay include single isomer R-beta-hydroxybutyrate and/or polymerR-beta-hydroxybutyrate. In some implementations, beta-hydroxybutyratemay be administered with 1,3-butanediol, ethyl acetoacetate, ethylbeta-hydroxybutyrate.

The beta-hydroxybutyrate may include racemic mixtures and/or individualisomers of betahydroxy-butyrate. In some implementations, one or morespecific chiralities of beta-hydroxybutyrate may be utilized. Forexample, R-beta-hydroxybutyrate (also referred to asD-beta-hydroxybutyrate), S-beta-hydroxybutyrate (also referred to asL-beta-hydroxybutyrate), and/or mixtures (e.g., raecemic mixtures)thereof may be utilized. In some implementations, R-beta-hydroxybutyratemay be included in the composition (e.g., a more purified form ofR-beta-hydroxybutyrate rather than D,L-beta-hydroxybutyrate). Forexample, R-beta-hydroxybutyrate may include less than approximately 10percent, less than approximately 5 percent, or less than approximately 1percent L-beta-hydroxybutyrate. R-beta-hydroxybutyrate may have agreater bioavailability than other chiralities of beta-hydroxybutyrate.R-beta-hydroxybutyrate may have a greater impact on a health of anindividual (e.g., due to decreased side effects; increase ketone levels,weight loss, mental acuity, fat loss, etc.) than L-beta-hydroxybutyrateand/or D,L-beta-hydroxybutyrate. In some implementations,R-beta-hydroxybutyrate may cause improvements in health not capable byL-beta-hydroxybutyrate and/or D,L-beta-hydroxybutyrate.R-beta-hydroxybutyrate may have less impurities due to manufacturing,such as less crotonic acid (e.g., which can be harmful to individuals),than other forms of beta-hydroxybutyrate (e.g., L-beta-hydroxybutyrateand/or D,L-beta-hydroxybutyrate). In some implementations,R-beta-hydroxybutyrate may be more capable of binding with othercompounds (e.g., purine, lysine, potassium, and/or other amino acids;dihydroberberine; etc.) to deliver the beta-hydroxybutyrate to a human.Thus, R-beta-hydroxybutyrate (e.g., greater than 90 percent purity ofR-beta-hydroxybutyrate and less than 10 percent L-beta-hydroxybutyrate)and/or mixtures with R-beta-hydroxybutyrate may be administered tohumans. In some implementations, unexpectedly, a smaller amount ofR-beta-hydroxybutyrate may be as pharmaceutically effective (e.g., inincreasing and/or maintaining weight loss; in increasing and/ormaintaining elevated ketone levels, etc.) or more pharmaceuticallyeffective as D,L-beta-hydroxybutyrate (e.g., raecemic mixture of D- andL-beta-hydroxybutyrate). For example, approximately half an amount ofR-beta-hydroxybutyrate may be administered to achieve the approximatelythe same efficacy as D,L-beta-hydroxybutyrate and/orL-beta-hydroxybutyrate. The R-beta-hydroxybutyrate may be morebioavailable than other chiralities of beta-hydroxybutyrate and thusallow a smaller effective amount than other chiralities. Thus, byutilizing R-beta-hydroxybutyrate, the administration amount ofbeta-hydroxybutyrate to be reduced (e.g., when compared to theadministration amount of D,L-beta-hydroxybutyrate) while providing apharmaceutically effective amount, such as (e.g., for weight loss and/ormaintenance; for elevating and/or maintaining blood ketone levels).Reducing the amount of beta-hydroxybutyrate, when thebeta-hydroxybutyrate is provided in salt form, may reduce a user'sintake of the cation of the salt (e.g., sodium, potassium, etc.). Sinceintake of some of these cations in beta-hydroxybutyrate salts, such assodium, potassium, magnesium, and calcium, in amounts greater than apredetermined recommended amount may cause health problems (e.g., organdamage, gastrointestinal problems, etc.), reducing the amount ofbeta-hydroxybutyrate salt by using R-beta-hydroxybutyrate may inhibitside effects and/or health problems associated salts combined withbeta-hydroxybutyrate administration in users.

In some implementations, a pharmaceutically effective amount ofR-beta-hydroxybutyrate may be administered in an individual to promoteand/or maintain ketosis, cause weight loss and/or manage weight, and/orincrease blood ketone levels. For example, approximately 0.1 g toapproximately 50 g of R-beta-hydroxybutyrate may be administered to anindividual. In some implementations, approximately 0.1 g toapproximately 15 g of R-beta-hydroxybutyrate may be administered to anindividual. In some implementations, approximately 1 g to approximately10 g of beta-hydroxybutyrate may be administered, for example, once aday to 5 times a day (e.g., to administer up to 50 g ofbeta-hydroxybutyrate). The administration may cause weight loss and/ormaintenance; elevated beta-hydroxybutyrate levels in the blood;elevated, reduced, and/or maintenance of blood ketone levels; inductionand/or maintenance of ketosis; and/or reduction; improve mental acuity;improve focus; improve energy; improve cognitive function; reducetraumatic brain injury; improve diabetes; improve glucose tolerance;decrease blood glucose levels; reduce neurological disorders and/orsymptoms thereof; improve cancer and/or symptoms thereof; improveinflammatory conditions; suppressing appetite; improve symptomsassociated with aging; provide anti-glycation affects; improve epilepsyand/or symptoms thereof; improve depression and/or symptoms thereof;improve performance; improve strength; increase muscle mass; increasefat loss; improve body composition; improve energy; improve focus;improve cognitive function; improve mood and/or well-being; and/orcombinations thereof. The beta-hydroxybutyrate (e.g.,R-beta-hydroxybutyrate) may be administered in healthy and not healthyindividuals (e.g., individuals with diseases and/or disorders).

In some implementations, the beta-hydroxybutyrate, such asR-beta-hydroxybutyrate, may be administered with and/or coupled to acompound such as an amino acid. For example beta-hydroxybutyrate may becoupled to (e.g., chemically bonded to) amino acids, such as leucine,lysine, arginine, histidine, ornithine, creatine, agmatine, citrullineand/or combinations thereof. In some implementations,R-beta-hydroxybutyrate may be utilized rather than other chiralitiessince R-beta-hydroxybutyrate may be more easily bound to leucine,purine, lysine, and/or other amino acids. Administration ofbeta-hydroxybutyrate that is coupled to an amino acid may reduce theintake of cations associated with beta-hydroxybutyrate salts (e.g.,which may inhibit side effects associated with administration) and/orallow administration of another compound that has health benefits (e.g.,administration of some amino acid may promote smooth muscle growthand/or cell repair). In some implementations, approximately 0.5 g toapproximately 10 g of amino acid may be administered with abeta-hydroxybutyrate. For example, less than approximately 50 g ofR-beta-hydroxybutyrate and less than approximately 60 mg of an aminoacid, such as leucine, may be administered daily. In someimplementations, approximately 0.5 g to approximately 2 g of an aminoacid, such as leucine, may be administered with a beta-hydroxybutyrate.For example, approximately the composition administered may includeapproximately 0.1 to approximately 7 g R-beta-hydroxybutyrate andapproximately 1-3 g of leucine. The R-beta-hydroxybutyrate and theleucine may be a mixture; administered separately and proximate intiming; a complex, and/or administered in any other appropriate manner.

In some implementations, the composition may includeR-beta-hydroxybutyrate salt and beta-hydroxybutyrate-amino acid complex(e.g., beta-hydroxybutyrate bound to amino acid, such asR-beta-hydroxybutyrate-leucine complex). For example, an individual maybe administered a first weight amount of sodium beta-hydroxybutyrate anda second weight amount of beta-hydroxybutyrate amino-acid complex. Thefirst amount and the second amount may be different or the same.

In some implementations, the beta-hydroxybutyrate composition mayinclude beta-hydroxybutyrate salt and beta-hydroxybutyrate esters. Forexample, an individual may be administered a first weight amount ofsodium beta-hydroxybutyrate and a second weight amount ofbeta-hydroxybutyrate ester. The first amount and the second amount maybe different or the same. The beta-hydroxybutyrate salt and thebeta-hydroxybutyrate ester may be a bound complex, a mixture ofcompounds, and/or separately administered approximately concurrently. Insome implementations, the beta-hydroxybutyrate ester may be in powderedform (e.g., plated beta-hydroxybutyrate ester), liquid and/or gel form.The combination of beta-hydroxybutyrate salt and beta-hydroxybutyrateester during administration may allow less salt to be utilized whileproducing a result (e.g., weight maintenance and/or loss; enhancedand/or maintained ketosis; elevated blood ketone levels; blood glucosereduction and/or maintenance; increase in energy; increase in mood;increase in performance; and/or increase in cognitive function). In someimplementations, elevated ketone levels (e.g., elevated blood ketonelevels) may increase energy, mood, performance, and/or cognitivefunction in users. For example, the administration of the first amountof beta-hydroxybutyrate salt may cause a first level of blood ketonelevel, which may be maintained by processing of the second amount of thebeta-hydroxybutyrate ester (e.g., as the body of the individualprocesses the beta-hydroxybutyrate ester the level ofbeta-hydroxybutyrate in the blood, and thus blood ketone level, may alsoincrease over time to enhance and/or maintain the initial elevationcaused by of the administered beta-hydroxybutyrate salt.). For example,a ratio of beta-hydroxybutyrate to beta-hydroxybutyrate ester may beapproximately 1 beta-hydroxybutyrate salt: approximately 1beta-hydroxybutyrate ester to approximately 1 beta-hydroxybutyrate salt:approximately 20 beta-hydroxybutyrate ester. The ratio ofbeta-hydroxybutyrate to beta-hydroxybutyrate ester may be approximately20 beta-hydroxybutyrate salt: approximately 1 beta-hydroxybutyrate esterto approximately 1 beta-hydroxybutyrate salt: approximately 20beta-hydroxybutyrate ester. In some implementations, a ratio ofbeta-hydroxybutyrate to beta-hydroxybutyrate ester may be approximately1 beta-hydroxybutyrate salt: approximately 1 beta-hydroxybutyrate esterto approximately 1 beta-hydroxybutyrate salt: approximately 5beta-hydroxybutyrate ester.

Related compounds that may be included as beta-hydroxybutyrate in thecomposition may include derivatives of beta-hydroxybutyrate, includeesters of (R)-3-hydroxybutyrate and oligomers of (R)-3-hydroxybutyrate.For example, beta-hydroxybutyrate esters derived from alcohols, such asaltrose, arabinose, dextrose, erythrose, fructose, galactose, glucose,glycerol, gulose, idose, lactose, lyxose, mannose, ribitol, ribose,ribulose, sucrose, talose, threose, xylitol, xylose, galactosamine,glucosamine, mannosamine, N-acetylglucosamine, mannitol, sorbitol,threitol, (S)-1,2-propanediol and/or (R)-1,3-butanediol. In someimplementations, a derivative of the beta-hydroxybutyrate may includestructures of (R)-3-hydroxybutyric acid and an exemplary ester thereof(a glycerol monoester). The R chirality of the derivatives may beselected for inclusion in the composition in some implementations (e.g.,to deliver R-beta-hydroxybutyrate with the administration of thecompound).

In some implementations, butyrate, beta-hydroxybutyrate (e.g.,R-beta-hydroxybutyrate), related compounds, and/or combinations thereofmay be administered along with one or more additional compounds. Theadditional compounds may or may not be capable of independentlyincreasing ketone levels, maintaining ketone levels, inducing ketosis,and/or maintaining ketosis. For example, additional compounds capable ofindependently increasing blood ketone levels may include short chainfatty acids (e.g., fatty acid with between 2 carbons than 6 carbons),short chain triglycerides (e.g., triglycerides with less than 6carbons), medium chain fatty acids (e.g., fatty acid with 6-12 carbons),medium chain triglycerides (e.g., triglycerides with 7-12 carbons), longchain fatty acids (e.g., fatty acids with more than 12 carbons), longchain triglycerides (e.g., triglycerides with more than 12 carbons),and/or combinations thereof. In some implementations, short chain fattyacids and/or triglycerides may include acetate, propionate, and/orbutyrate. Medium chain fatty acids and/or triglycerides may includelauric acid and/or coconut oil, coconut milk powder, fractionatedcoconut oil, isolated hexanoic acid, isolated octanoic acid, isolateddecanoic acid, ethoxylated triglyceride, triglyceride derivativesthereof, aldehyde triglyceride derivatives thereof, monoglyceridederivatives thereof, diglyceride derivatives thereof, triglyceridederivatives thereof, and/or alkyl esters thereof. Long chain fatty acidsand/or triglycerides may include dairy products and/or palm oil. In someimplementations, a compound including R-beta-hydroxybutyrate and anadditional compound that is independently capable of increasing ketonelevels may increase ketone levels greater than merely the capability ofeach component individually (e.g., greater than an additive increase).

For example, a pharmaceutically effective amount of one or more shortchain fatty acids and/or one or more short chain triglycerides (e.g.,butyric acid and/or butyrate) may be administered with apharmaceutically effective amount of beta-hydroxybutyrate. In someimplementations, approximately 1 g to approximately 10 g ofbeta-hydroxybutyrate and approximately 0.1 g to approximately 50 g ofshort chain fatty acid and/or triglyceride may be administered from oncea day to approximately 5 times a day. In some implementations,approximately 1 g to approximately 3 g of beta-hydroxybutyrate andapproximately 1 g of short chain fatty acid and/or triglyceride may beadministered from once a day to approximately 5 times a day. In someimplementations, the short chain fatty acid and/or triglyceride mayinclude butyrate or derivatives of butyrate. Butyrate and/or derivativesof butyrate may be administered with and/or without beta-hydroxybutyrateto manage metabolic conditions, such as ketosis, and/or for otherappropriate therapeutic purposes. Administered butyrate may be convertedto beta-hydroxybutyrate in humans, and thus may increase the amount ofbeta-hydroxybutyrate delivered to the user. In some implementations,administration of butyrate and beta-hydroxybutyrate may promote hGHsynthesis, improve basal and GHRH-induced hGH-secretion, increase musclefiber cross-sectional area, inhibit intramuscular fat accumulation;reduce fat mass in a user; improve glucose metabolism; increase markersof mitochondrial biogenesis in skeletal muscle and/or whole-body oxygenconsumption; reduced markers of oxidative stress and apoptosis andaltered antioxidant enzyme activity; cause butyrate enhancedintracellular free cytosolic calcium levels (e.g., by acting throughGPR41 and 43); increase beta-hydroxybutyrate levels; and/or supportbarrier function(s) in the gut and/or reduce inflammation associatedwith ulcerative colitis. Since butyrate is processed by the body toprovide beta-hydroxybutyrate, the delivery of beta-hydroxybutyrate viathe butyrate may supplement the directly administeredbeta-hydroxybutyrate to maintain a level of beta-hydroxybutyrate in theblood (e.g., to promote ketosis, weight loss and/or management, etc.).

However, butyrate and/or butyric acid may not be palatable toindividuals (e.g., since the odor and taste are often compared tovomit). Thus, in some implementations, butyrate and/orbeta-hydroxybutyrate (e.g., R-beta-hydroxybutyrate) may be processed toreduce organoleptic reactions. For example, the butyrate and/orbeta-hydroxybutyrate (e.g., R-beta-hydroxybutyrate) may be encapsulated,microemulsion, liposomes, agglomeration, masking/flavoring technologies,and/or otherwise processed as appropriate to reduce organolepticreactions from individuals administered the described composition(s). Insome implementations, microencapsulated butyrate, beta-hydroxybutyrate,and/or butyric acid may be utilized (e.g., in combination withbeta-hydroxybutyrate). Using microencapsulated butyrate,beta-hydroxybutyrate, and/or butyric acid (e.g., when compared withusing unencapsulated forms) may increase individual satisfaction and/orcompliance with an administration schedule since odor from the butyrateand/or butyric acid may be reduced and/or removed. The microencapsulatedbutyrate, beta-hydroxybutyrate, and/or butyric acid may be a freeflowing granular powder; dispersible in water; stable in acidic watersolution for 30 minutes; allow controlled release in stomach and/orsmall intestines; inhibit glucose response (e.g., to any addedmaterials); and/or allow delivery of a high butyrate content (e.g.,around 70%).

In some implementations, a pharmaceutically effective amount of butyratemay be administered via triglyceride tributyrin (e.g., glyceryltributyrate or tributyrin). The butyrate via triglyceride tributyrin maybe administered separately and/or in conjunction with one or more of theother described compounds (e.g., beta-hydroxybutyrate, fatty acidsand/or esters, etc.). For example, up to approximately 200 mg/kg of theindividual may be administered (e.g., up to 3 times daily).Administration of the tributyrin may allow a delayed release of butyrateto the body as the tributyrin is processed by the body of theindividual. The tributyrin may be unencapsulated and/or encapsulated(e.g., microencapsulated).

In some implementations, administration of beta-hydroxybutyrate and ashort chain compound (e.g., short chain fatty acid and/or short chaintriglyceride) may unexpectedly increase beta-hydroxybutyrateconcentrations in the blood more than the administration of similaramounts of beta-hydroxybutyrate and medium chain compounds (e.g., shortchain fatty acid and/or short chain triglyceride) and/or may increasebeta-hydroxybutyrate concentrations in the blood more than eachcomponent individually.

In some implementations, a pharmaceutically effective amount ofbeta-hydroxybutyrate may be administered with a pharmaceuticallyeffective amount of long chain fatty acid and/or triglyceride. Forexample, 0.1-50 g of beta-hydroxybutyrate and 0.1 to 50 g of long chainfatty acid may be administered to an individual between 1-5 times a day.In some implementations, approximately 1 g to approximately 3 g ofbeta-hydroxybutyrate and approximately 1 g of long chain fatty acidand/or triglyceride may be administered from once a day to approximately5 times a day.

In some implementations, beta-hydroxybutyrate, short chain compound(s)(e.g., fatty acids and/or triglycerides, butyrate), and/or medium chaincompound(s) (e.g., fatty acids and/or triglycerides) may be administeredapproximately simultaneously and/or sequentially to an individual. Forexample, approximately 0.1 g to approximately 50 g beta-hydroxybutyrate,approximately 0.1 g to approximately 50 g short chain triglyceride, andapproximately 0.1 g to approximately 50 g medium chain fatty acid suchas lauric acid and/or coconut oil may be administered between 1-5 timesa day. In some implementations, approximately 1 g to approximately 3 gof beta-hydroxybutyrate and approximately 1 g of short chain fatty acidand/or triglyceride and/or approximately 1 g of medium chain fatty acidand/or triglyceride may be administered from once a day to approximately5 times a day. In some implementations, approximately 0.1 g toapproximately 20 g beta-hydroxybutyrate (e.g., salts, esters, isomers,and/or other appropriate forms) may be administered in humans. In someimplementations, approximately 0.1 g to approximately 20 g butyrate maybe administered in humans.

In some implementations, other compounds, such as compounds capable ofindependently decreasing glucose levels, may be administered withbeta-hydroxybutyrate, such as berberine and/or associated metabolites(e.g., dihydroberberine and/or tetrahydroberberine). U.S. patentapplication Ser. No. 15/491,933 entitled “ADMINISTRATION OFDIHYDROBERBERINE” to Lowery et al, filed Apr. 19, 2017 and U.S.Provisional Patent Application No. 62/324,794, entitled “ADMINISTRATIONOF DIHYDROBERBERINE” to Lowery et al, filed Apr. 19, 2016, describedihydroberberine administration with ketone sensitizers such asbeta-hydroxybutyrate, and is hereby fully incorporated herein. In someimplementations, one or more beta-hydroxybutyrates and/or othercompounds described herein may be utilized as a ketone sensitizer withthe dihydroberberine.

In some implementations, directly administering beta-hydroxybutyrateplus another compound that is processed to deliver beta-hydroxybutyrate(e.g., beta-hydroxybutyrate ester, beta-hydroxybutyrate polymer,butyrate, other appropriate compounds, and/or combinations thereof) overtime may allow a first level of beta-hydroxybutyrate in the blood to bemaintained over a period of time. For example, since the directlyadministered beta-hydroxybutyrate may elevate blood beta-hydroxybutyratelevels to a first concentration and this concentration may beapproximately maintained over a period of time by providing additionalbeta-hydroxybutyrate via another compound administered approximatelyconcurrently (e.g., short chain fatty acid and/or triglyceride,beta-hydroxybutyrate ester, beta-hydroxybutyrate polymer,beta-hydroxybutyrate amino acid complex, etc.).

In some implementations, one or more other compounds may be administered(e.g., included in the composition and/or separately administered) withthe butyrate (e.g., microencapsulated butyrate), beta-hydroxybutyrate(e.g., R-beta-hydroxybutyrate) and/or fatty acids or esters, such asshort chain fatty acids. Other compositions may include, but are notlimited to amino acids, amino acid metabolites, vitamins, minerals,coconut milk powder, flavorings, colorings, binders, electrolytes,tetrahydrobiopeterin, nucleic acids, alpha-ketoglutaric acid, alphalipoic acid, nutritional co-factors, beta-methyl-beta-hydroxybutyrate,arginine alpha-ketoglutarate, R-alpha lipoic acid, thiamine, NAD+, NADH,riboflavin, FAD+, FADH, riboflavin-5-phosphate, niacin, nicotinic acid,niacinamide, inositol hexanicotinate, pyridoxine, pyridoxal,pyridoxamine, ascorbic acid and ascorbate salts, citric acid, malicacid, sodium benzoate, Pyridoxal-5-Phosphate, methylcobalamin,cyanocobalamin, adenosylcobalamin, hydroxycobalamin, pantothenic acid,pantetheine, potassium sorbate, acesulfame K, aspartame, sucralose,stevia, monk fruit extract, allulose, prebiotic fibers, XOS, GOS, MOS,IMO, LOS, xanthan gum and other organic gums/thickeners/suspensionagents, and combinations thereof.

In various implementations, administration of a composition thatincludes beta-hydroxybutyrate may improve the health of an individual.R-beta-hydroxybutyrate may be capable of providing a greater impact onthe health of an individual than D,L-beta-hydroxybutyrate and/orL-beta-hydroxybutyrate. Although previously unknown,L-beta-hydroxybutyrate may decrease the effectiveness ofR-beta-hydroxybutyrate with respect to at least a portion of the impacton health. With respect to some impacts on health,L-beta-hydroxybutyrate may have no impact on health. In someimplementations, even double the amount of D,L-beta-hydroxybutyrate maynot achieve some of the same results (e.g., in health improvement) asR-beta-hydroxybutyrate. Thus, unexpectedly administration ofD,L-beta-hydroxybutyrate rather than R-beta-hydroxybutyrate may not havethe same impact on health and/or have less of an impact on health of anindividual. For example, administration of a composition that includesR-beta-hydroxybutyrate (e.g., and/or other compounds) may improve and/ormaintain an individual's health.

Administration of R-beta-hydroxybutyrate as described may increaselifespan in individuals following a dietary plan (e.g., standardAmerican low-fat, ketogenic, Paleo, Mediterranean, etc.) and/or notfollowing a dietary plan. For example, approximately 10 g ofR-beta-hydroxybutyrate to approximately 30 g R-beta-hydroxybutyrate maybe administered to increase lifespan. In some implementations, otherappropriate amounts of R-beta-hydroxybutyrate may be included in thecomposition.

In some implementations, administration of R-beta-hydroxybutyrate maytreat and/or lesson the impact of symptoms of disease(s) and/ordisorders, such as diseases that impact cognitive function.Administration of R-beta-hydroxybutyrate may increase motor function inindividuals with Parkinson's disease. For example, approximately 5 g ofR-beta-hydroxybutyrate to approximately 15 g R-beta-hydroxybutyrate maybe administered to increase motor function. In some implementations,other appropriate amounts of R-beta-hydroxybutyrate may be included inthe composition.

Administration of R-beta-hydroxybutyrate may increase fat loss. Unlikewith conventional diets, in which weight loss often comes from decreasesin water retention and/or muscle mass, administration ofR-beta-hydroxybutyrate may cause decreases in fat loss (see for example,FIG. 5B). In addition, administration of R-beta-hydroxybutyrate maydecrease levels of LPL in the body, and thus reduce or inhibit fatstorage and/or encourage existing fat storage utilization by the body.For example, approximately 1 g of R-beta-hydroxybutyrate toapproximately 20 g R-beta-hydroxybutyrate may be administered to causefat loss and/or reduce fat storage. In some implementations, otherappropriate amounts of R-beta-hydroxybutyrate may be included in thecomposition. Administration of R-beta-hydroxybutyrate may allow fat lossgreater than 5 kg while maintaining lean mass. In some implementations,the administration of R-beta-hydroxybutyrate increases the amount of fatused as fuel.

In some implementations, administration of R-beta-hydroxybutyrate mayimprove and/or maintain health markers such as C-reactive protein and/orfasting glucose. Administration of R-beta-hydroxybutyrate may decreaseinflammation (e.g., as shown by C-reactive protein levels).Administration of R-beta-hydroxybutyrate may decrease fasting glucose.For example, approximately 3 g of R-beta-hydroxybutyrate toapproximately 20 g R-beta-hydroxybutyrate may be administered to cause areduction in and/or maintain a low fasting glucose. In someimplementations, other appropriate amounts of R-beta-hydroxybutyrate maybe included in the composition. In some implementations,R-beta-hydroxybutyrate may be administered with one or more othercompounds to decrease glucose levels and/or sensitivity. For example,administration of a composition of R-beta-hydroxybutyrate and aberberine, such as dihydroberberine, may cause reduce and/or maintainlow fasting glucose. Administration of a composition ofR-beta-hydroxybutyrate and a berberine, such as dihydroberberine, maycause reduce and/or maintain low glucose levels. In someimplementations, less than approximately 15 g of R-beta-hydroxybutyratemay be administered with less than approximately 600 mg ofdihydroberberine.

Administration of R-beta-hydroxybutyrate may decrease ketone levels (seee.g., FIGS. 11A and 11B). Decreasing blood ketone levels may increaseweight loss, maintain weight loss, improve performance, increase mentalacuity, and/or have other health improvement and health maintenancefeatures. For example, even at levels less than 10 g (e.g.,approximately 5 g), administration of R-beta-hydroxybutyrate maydecrease ketone levels while L-R-beta-hydroxybutyrate does not, andD,L-beta-hydroxybutyrate does not to the same extent.R-beta-hydroxybutyrate may increase blood ketone levels 5 times as muchas similar administration amounts of D,L-beta-hydroxybutyrate. By beingable to decrease an amount of R-beta-hydroxybutyrate (e.g., whencompared with administering D,L-beta-hydroxybutyrate) administered andachieve the same results, a decrease in an amount cation (e.g., sodium,potassium, etc.) may also be administered. Since some individuals mayprefer and/or may not tolerate higher dosages of the cations of theR-beta-hydroxybutyrate salt, utilizing R-beta-hydroxybutyrate may allowadministration to more people, increase user satisfaction, and/ordecrease side effects (e.g., associated with additional consumption ofthese cations). In some implementations, approximately 0.1 g ofR-beta-hydroxybutyrate to approximately 10 g R-beta-hydroxybutyrate maybe administered to increase blood ketone levels. Approximately 0.5 g ofR-beta-hydroxybutyrate to approximately 3 g R-beta-hydroxybutyrate maybe administered to maintain blood ketone levels. In someimplementations, other appropriate amounts of R-beta-hydroxybutyrate maybe included in the composition.

Administration of R-beta-hydroxybutyrate may increase performance anddecrease perceived exertion (e.g., as opposed to when administeredD,L-beta-hydroxybutyrate). For example, approximately 3 g ofR-beta-hydroxybutyrate to approximately 15 g R-beta-hydroxybutyrate maybe administered to increase performance and/or decrease perceivedexertion. In some implementations, other appropriate amounts ofR-beta-hydroxybutyrate may be included in the composition.

In various implementations, oral administration ofR-beta-hydroxybutyrate may increase muscle protein synthesis whileD,L-beta-hydroxybutyrate does not increase muscle protein synthesis. Forexample, approximately 10 g of R-beta-hydroxybutyrate to approximately30 g R-beta-hydroxybutyrate may be administered to increase muscleprotein synthesis. In some implementations, other appropriate amounts ofR-beta-hydroxybutyrate may be included in the composition.

In some implementations, the administration of R-beta-hydroxybutyrate,unlike D,L-beta-hydroxybutyrate may decrease perceived hunger and/orincrease satiety) which may inhibit overeating and thus promote weightloss (see e.g., FIGS. 13A and 13B). In some implementations, theadministration of R-beta-hydroxybutyrate, unlikeD,L-beta-hydroxybutyrate may increased perceived energy (see e.g., FIG.13C).

In some implementations, administration of R-beta-hydroxybutyrateincreased mental acuity. For example, approximately 0.1 g ofR-beta-hydroxybutyrate to approximately 10 g R-beta-hydroxybutyrate maybe administered to increase mental acuity. In some implementations,other appropriate amounts of R-beta-hydroxybutyrate may be included inthe composition.

In some implementations, the administration of R-beta-hydroxybutyratemay be supplemented with other forms of beta-hydroxybutyrate, butyricacid, and/or butyrate.

In some implementations, the composition administered may includeR-beta-hydroxybutyrate. The amount of R-beta-hydroxybutyrate included inthe composition may be selected to obtain a result (e.g., induceketosis; maintain ketosis; increase ketone levels, mental acuity,strength, etc.) upon administration (e.g., a pharmaceutically effectiveamount may be administered at a dosage and/or over a predetermined timeperiod). In some implementations, the dosage and/or frequency of dosagemay vary over time (e.g., initial vs a lower dosage for maintenance,vary based on time of day, vary based on whether taken with or without ameal, etc.).

The R-beta-hydroxybutyrate in the composition may include anyappropriate and/or appropriate number of forms, such as salts,derivatives (e.g., esters), polymers, and/or complexes with othercompounds. For example, the composition may includeR-beta-hydroxybutyrate salt (e.g., sodium R-beta-hydroxybutyrate,magnesium R-beta-hydroxybutyrate, and/or potassiumR-beta-hydroxybutyrate) and/or another form of R-beta-hydroxybutyrate(e.g., ester, polymer, complex, etc.). In some implementations, thecomposition may include an ester of R-beta-hydroxybutyrate. Thecomposition may include an amino acid (e.g., separate and/or complexedwith R-beta-hydroxybutyrate), such as leucine. The use of non-salt baseR-beta-hydroxybutyrate may increase user satisfaction (e.g., by reducingthe cation, such as sodium and/or potassium, load due to ingestion ofthe composition; by decreasing side effects; etc.), increase theapplicability of the administration (e.g., since users sensitive to thecations of the R-beta-hydroxybutyrate salts may be less sensitive to thenon-salt and/or lower salt plus non-salt forms of the composition). Theadministration of the composition may increase blood ketone levels,induce ketosis, maintain blood ketone levels, maintain ketosis, increasehealth, increase strength, increase mental acuity, etc. In someimplementations, a first composition that includesR-beta-hydroxybutyrate salt may be administered to cause a first impact(e.g., induce ketosis, quickly increase mental acuity, quickly increasestrength, etc.) and a second composition that includes non-saltsR-beta-hydroxybutyrate (e.g., esters, polymers, complexes, etc.) and/orlower levels of R-beta-hydroxybutyrate salt may be utilized to cause asecond impact (e.g., maintain ketosis, maintain mental acuity, maintainincreased strength, etc.).

In some implementations, the form(s) of R-beta-hydroxybutyrate includedin the may be selected based on the delivery form. For example, in someforms of food products the composition may includeR-beta-hydroxybutyrate polymer (e.g., due to taste since increasedcations like sodium may decrease palatability; due to nutrition sinceincreased cations such as sodium may decrease nutrition; due tomixability, etc.). As another example, the composition may includeR-beta-hydroxybutyrate salts or other forms (e.g., microencapsulated) toprovide quick dissolve powders.

In various implementations, a composition may includeR-beta-hydroxybutyrate. The R-beta-hydroxybutyrate may be in anyappropriate form (e.g., salt, ester, polymer, complex, derivativesthereof, and/or combinations thereof). The composition may include oneor more additional compositions. Additional composition(s) may becapable of independently increasing blood ketone levels (e.g., fattyacids or esters, berberine or berberine metabolites such asdihydroberberine, etc.). Additional composition(s) may be capable ofindependently decreasing blood glucose levels (e.g., berberine orberberine metabolites such as dihydroberberine). In someimplementations, additional compounds may not be capable ofindependently increasing blood ketone levels and/or decreasing bloodglucose levels (e.g., additives, flavorings, colorings, minerals,vitamins, binders, anti-caking agents, etc.). The composition may beadministered in an effective amount to cause a predetermined healthimpact (e.g., predetermined level of ketosis, blood ketone level, mentalacuity, strength increase, perceived energy, fat loss, weight loss,etc.). The composition may be administered to an individual in apredetermined amount and/or different amounts over an administrationschedule. In some implementations, once a first criteria is satisfied(e.g., period of time, number of doses, predetermined health impact),the dosage amount may be altered. For example, first dose(s) of thecomposition may be administered to cause a predetermined health impactand additional lower dose(s) of the composition may be administered tomaintain the predetermined health impact (e.g., caused in part by thefirst doses).

The composition may be administered in any appropriate delivery form(e.g., tablet; capsule; food products such as powdered products that canbe mixed into food, mixed into beverages, and/or consumed directly;beverage product; etc.). The composition may be administered accordingto any appropriate schedule (e.g., periodic dosages, dosages as userdesires, etc.). The administration schedule may inhibit administrationthat elevates blood ketone levels too high, decreases blood glucoselevels too low, and/or causes an individual to consume a dosage thatsubstantially elevates the risk of adverse and/or side effects, in someimplementations.

In some implementations, the composition may include a long actingcomponent and/or be long-acting. For example, since the body digestspolymers and/or esters of beta-hydroxybutyrate (e.g.,R-beta-hydroxybutyrate), the delivery of R-beta-hydroxybutyrate may beslower than a digestion of a beta-hydroxybutyrate salt (e.g.,R-beta-hydroxybutyrate salt). In some implementations, the compositionmay include a R-beta-hydroxybutyrate and a long actingR-beta-hydroxybutyrate form (e.g., polymer, ester, coated and/orprocessed form to provide slow release). In some implementations, afirst dose(s) may include at least one non-long acting form ofbeta-hydroxybutyrate and a second dose(s) may include at least onelong-acting form of beta-hydroxybutyrate. The first dose(s) may beadministered to cause a predetermined health impact and the seconddose(s) may be administered to maintain the caused predetermined healthimpact. In some implementations, users may select the appropriate dosebased on user preference and/or properties (e.g., a user on a ketogenicdiet may chose the second dose since the user may already be inketosis).

EXAMPLES Example 1

4 subjects were administered 10 mg of sodium D,L-beta-hydroxybutyrateand their blood ketone level in mmol/dL was tested after administration,30 minutes, 60 minutes, 90 minutes, 120 minutes, and 180 minutes afteradministration. Each subject was also subsequently studied afteradministration of 10 g of sodium R-beta-hydroxybutyrate and 5 g ofsodium R-beta-hydroxybutyrate. As illustrated in FIG. 1, on average,administration of 5 mg of sodium R-beta-hydroxybutyrate producedapproximately the same blood ketone level in a subject after 30 minutes,60 minutes, 90 minutes, 120 minutes, and 180 minutes as 10 g ofD,L-beta-hydroxybutyrate.

Example 2

Three subjects were administered 10 grams of medium chain triglyceridesand 8 grams of beta-hydroxybutyrate and blood beta-hydroxybutyrateconcentration was monitored over time. The same subjects were lateradministered 10 grams of short chain triglycerides and 8 grams ofbeta-hydroxybutyrate and blood beta-hydroxybutyrate concentration wasmonitored. FIG. 2 illustrates an average blood ketone concentration(mmol/L) for the subjects after administration, after 30 minutes, after60 minutes, after 90 minutes, after 120 minutes, and after 180 minutes.As illustrated in FIG. 2, administration of the beta-hydroxybutyratewith a short chain compound (illustrated in red bars or the second barin each set), such as short chain triglyceride, caused greater elevationof blood ketone levels than administration of a similar amount of mediumchain compound (illustrated in the blue bars or first bar in each set)at least after administration, after 30, 60, 90 minutes, and 180minutes. Thus, administration of short chain compounds (e.g., fattyacids and/or triglycerides) may unexpectedly allow a smaller weightamount, when compared to medium chain compounds, to be administered toproduce the same result (e.g., blood ketone level, weight loss, weightmanagement, etc.) and/or allow greater results (e.g., when compared withsimilar amount of medium chain compounds).

Example 3

Sixteen rats (Fischer 344 rats) were studied for the effect ofR-beta-hydroxybutyrate on lifespan. A first grouping of eight rats werefed an equivalent to a low-fat standard American diet and a secondgrouping of eight rats were fed the same equivalent to a low-fatstandard American diet and supplemented with R-beta-hydroxybutyrate salt(e.g., sodium R-beta-hydroxybutyrate). The second grouping of rats weresupplemented with the R-beta-hydroxybutyrate salt at middle age. FIG. 3illustrates the average lifespans of the groupings of rats. Asillustrated, at 20 months approximately half of the first grouping ofrats died on the standard diet while only 12.5% of the second groupingof rats had died at 20 months. Thus, the supplementation of rats dietswith R-beta-hydroxybutyrate increased lifespan for approximately in atleast approximately 38.5% of the rats. Since the rat study was performedas an approximation of impact in humans, the addition ofR-beta-hydroxybutyrate to a standard American low-fat diet may increaselifespan.

Example 4

An individual with Parkinson's disease was tested for motor functionwith and without administration of approximately 10 g ofR-beta-hydroxybutyrate salt. The testing included a right-eye visual andmotor performance apparatus to track motor function through eyemovements.

FIG. 4 illustrates chart illustrating the results of the motor skilltesting following an example implementation of administration ofR-beta-hydroxybutyrate. FIG. 4 illustrates average results for a similarnon-Parkinson's population, the patient pre-administration ofR-beta-hydroxybutyrate, and the patient post-administration ofR-beta-hydroxybutyrate. As illustrated, the administration ofR-beta-hydroxybutyrate increased motor function (e.g., approximately 30minutes after administration of the R-beta-hydroxybutyrate).

Example 5

An individual was administered 5 g of R-beta-hydroxybutyrate twice dailyfor 3 months. Xray absorptiometry was performed to determine the impactof the administration of R-beta-hydroxybutyrate on fat loss. FIG. 5Aillustrates a chart that shows the results after 3 months ofadministration. As illustrated, the individual experienced a greaterthan approximately 10% decrease in fat mass. FIG. 5B illustrates thatthe fat loss was sustained while maintaining lean mass. Thus, theR-beta-hydroxybutyrate may cause weight loss through fat loss ratherthan lean mass (e.g., muscle mass).

Example 6

A first grouping of 10 rats (labeled SC) were given a standard diet, asecond grouping of 10 rats (labeled KD) were given a ketogenic diet, athird grouping of 10 rats (labeled SC+MS) were on the standard diet butgiven a first dosage of R-beta-hydroxybutyrate salt (e.g., equivalent to5 g) and a fourth grouping was on the standard iet but given a seconddosage of R-beta-hydroxybutyrate salt (e.g., equivalent to 10 g). FIG. 6illustrates the average Lipoprotien lipase (LPL) in the rats. Since LPLis needed to transport fat into adipose tissue, lowering LPL levelswould inhibit fat storage and encourage usage of fat storages. Asillustrated, supplementation of a standard diet with even lower dosagesof R-beta-hydroxybutyrate decreases LPL levels and thus inhibits fatstorage.

Example 7

An individual with high C-reactive protein, which is associated withinflammation, was administered R-beta-hydroxybutyrate. Afteradministration, the C-reactive protein levels were substantially reduced(e.g., 62.5 to 4.4). In addition, fasting glucose was decreased (e.g.,104 to 95).

Example 8

Five healthy individual were given a 2 km time test (e.g., 4 cycles oflow to severely intense exercise on a wingate cycle ergometer) 30minutes after administration of a placebo, 10 g ofR-beta-hydroxybutyrate, and 10 g of R-beta-hydroxybutyrate. FIG. 7illustrates the average blood ketone levels and FIG. 8 illustrates thepercentage improvement over the administration of the placebo. Asillustrated, blood ketone levels unexpectedly increased more than doubleduring administration of R-beta-hydroxybutyrate when compared withadministration of D,L-beta-hydroxybutyrate. In addition, performance(e.g., improvement in time) increased by more than double duringadministration of R-beta-hydroxybutyrate when compared withD,L-beta-hydroxybutyrate. FIG. 9 illustrates the perceived exertionexperienced by the individuals. As illustrated, the individuals did notfeel an impact in perceived exertion after administration withD,L-beta-hydroxybutyrate as compared with the perceived exertionimprovement experienced after administration of R-beta-hydroxybutyrate.Thus, the R-beta-hydroxybutyrate has an unexpectedly impact on ketonelevels and performance.

Example 9

Individuals were given a standard diet or ketogenic diet. Someindividuals were administered R-beta-hydroxybutyrate (e.g., 10 g).R-beta-hydroxybutyrate was able to numerically increase superoxidedismutase 2 levels (SOD) in the brain which indicates greaterantioxidant capacity in the brain.

Example 10

Individuals were 5 g or 10 mg of R-beta-hydroxybutyrate,L-beta-hydroxybutyrate, or D,L-beta-hydroxybutyrate and blood ketonelevels were measured. FIGS. 10 and 11 illustrate the measured bloodketone levels. As illustrated, administration of R-beta-hydroxybutyratemay decrease ketone levels (see e.g., FIGS. 11A and 11B). The reductionof ketone levels occurs even when R-beta-hydroxybutyrate is administeredat a dosage of less than 10 g (e.g., approximately 5 g). In addition,unexpectly (e.g., since it was expected that both the D and L forms ofR-beta-hydroxybutyrate behaved in a similar manner), administration ofL-beta-hydroxybutyrate does not decrease blood ketones. Furthermore,unexpectedly, even D,L-beta-hydroxybutyrate does not lower blood ketonelevels to the same extent as R-beta-hydroxybutyrate. This indicates thatL-beta-hydroxybutyrate may block some of the impact ofR-beta-hydroxybutyrate, which is unexpected.

Example 11

10 subjects were administered approximately 5 g or 10 g ofD,L-beta-hydroxybutyrate or R-beta-hydroxybutyrate, and Respiratoryexchange ratio was examined (RER, a ratio of carbon dioxide/oxygen).Generally, a ratio of 1.0 indicates that 100% carbohydrate is used asfuel and at 0.7, 100% fat is used as fuel. As illustrated in FIG. 12A,at 10 g, R-beta-hydroxybutyrate administration reduces RER approximately3× more than D,L-beta-hydroxybutyrate. As illustrated in FIG. 12B, 5 gof R-beta-hydroxybutyrate is capable of achieving a result that evenmore D,L-beta-hydroxybutyrate is unable to (e.g.,D,L-beta-hydroxybutyrate increases RER by 17% rather than decreasingRER).

Example 12

Individuals were administered 5 g-10 g of D,L-beta-hydroxybutyrate orR-beta-hydroxybutyrate and tested for perceived hunger, satiety, andperceived energy. FIGS. 13A-13C illustrates the results of the testing.FIG. 13A illustrates perceived hunger, FIG. 13B illustrates perceivedsatiety, and FIG. 13C illustrates perceived energy. As illustrated inFIG. 13B, at 30 minutes post consumption R-beta-hydroxybutyrate improvedsatiety levels 2.3× better than DL-beta-hydroxybutyrate relative tobaseline levels. As illustrated in FIG. 13C, R-beta-hydroxybutyrateimproved perceived energy from 0 to 30 minutes post consumption bydouble that of D,L-beta-hydroxybutyrate. R-beta-hydroxybutyratesustained elevated perceived energy levels from 0 minutes at 60, 90, and120 minutes post consumption, as opposed to D,L-beta-hydroxybutyrate. Asillustrated, R-beta-hydroxybutyrate was able to raise perceived energyby 18% and sustain it for 2 hours post ingestion (e.g., more than 2times greater than the peak value of increase with theDL-beta-hydroxybutyrate)

Example 13

5 young (20s) resistance trained males lifting 50% of their 1-RM onBench Presses were tested before and after administration of 5 g ofR-beta-hydroxybutyrate or D,L-beta-hydroxybutyrate. FIGS. 14A-Billustrate the results of the testing. As illustrated,R-beta-hydroxybutyrate administration resulted in an 11% increase, whileDL-beta-hydroxybutyrate administration resulted in only a 2% decrease.Thus, R-beta-hydroxybutyrate experienced a greater than expected impactwhen compared with D,L-beta-hydroxybutyrate.

The individuals were also tested for power. FIG. 14C illustrates theresults of the testing (e.g., averages of power measurements). Asillustrated, R-beta-hydroxybutyrate administration increased minimumpower by 26%, while the DL-beta-hydroxybutyrate administration raisedpower by 2%.

Example 14

Individuals were tested for mental acuity before and afteradministration of 5-10 g of R-beta-hydroxybutyrate orD,L-beta-hydroxybutyrate. Circular Tracking testing (e.g., to assesstheir cognitive function) was performed and administration ofDL-beta-hydroxybutyrate (e.g., 10 g) caused no improvement while theR-beta-hydroxybutyrate (e.g., 10 g) administration caused approximately3% improvement in tracking accuracy. Vertical Tracking testing (e.g., toassess their cognitive function) was performed and administration ofD,L-beta-hydroxybutyrate (e.g., 10 g) improved performance by 4.6%,while the administration of R-beta-hydroxybutyrate (e.g., 10 g) improvedperformance by 13.8%, which is approximately 3 times greaterimprovement. Horizontal Saccades testing was performed (e.g., a saccadeis one eye movement and known to become significantly slower ifcognitive function declines and improve if cognitive function improves).In the horizontal saccades testing, performance improvements were 4times greater with the administration of R-beta-hydroxybutyrate (e.g., 5g) than with administration of D,L-beta-hydroxybutyrate (e.g., 13.8% vs.3.2%). Processing speed testing was performed (e.g, processing speed isconsidered a true measure of cognitive performance). Administration ofR-beta-hydroxybutyrate (e.g., 5 g) improved processing speed by 27.7%and only approximately 18% with administration of theDL-beta-hydroxybutyrate (e.g., 5 g). Response accuracy was also tested.Administration of R-beta-hydroxybutyrate (e.g., 5 g) increased accuracyby 37 percentage points when compared to 12.7% whenDL-beta-hydroxybutyrate was administered.

Thus, administration of R-beta-hydroxybutyrate increased mental acuitymore than a similar amount of D,L-beta-hydroxybutyrate. In fact, as thetesting revealed, the administration of R-beta-hydroxybutyrate increasedmental acuity often by than double when compared with a similar amountof D,L-beta-hydroxybutyrate.

Example 15

The compound for administration was prepared to include anR-beta-hydroxybutyrate amino acid complex. An R-beta-hydroxybutyrateAgmatine complex was prepared and an R-beta-hydroxybutyrate Argininecomplex was prepared. FIG. 15 illustrates the average blood ketonelevels achieved with the R-beta-hydroxybutyrate amino acid complex(e.g., an average of both complexes) when compared withD,L-beta-hydroxybutyrate. As illustrated, blood ketone levels are notonly more than double the blood ketone levels achieved with the samequantity of D,L-beta-hydroxybutyrate as R-beta-hydroxybutyrate aminoacid complex (e.g., 10 g), but they are more than an additive result ofa similar amount of R-beta-hydroxybutyrate and amino acid.

Use of the R-beta-hydroxybutyrate amino acid complex may reduce theamount of cation delivered (e.g. since the complex may deliver theR-beta-hydroxybutyrate rather than a R-beta-hydroxybutyrate salt). Thereduction of this cation may decrease side effects (e.g., from increasedsodium, potassium, and/or magnesium intake), increase user satisfaction,and/or increase the population that can tolerate the administration ofR-beta-hydroxybutyrate (e.g., since some individuals may not be capableof increasing loads of these cations due to underlying diseases and/ordisorder). The use of the R-beta-hydroxybutyrate amino acid complex mayalso allow a higher yield of R-beta-hydroxybutyrate to be administered(90.8% R-beta-hydroxybutyrate, 5% amino acid) when compared with asimilar weight of R-beta-hydroxybutyrate salt (e.g., average of 83%yield for BHB sodium).

Example 16

A composition for administration may include R-beta-hydroxybutyrate andan amino acid, such as Leucine. The R-beta-hydroxybutyrate and leucinemaybe complexed and/or mixed together for administration. TheR-beta-hydroxybutyrate and leucine may be administered separately butapproximately concurrently. FIG. 16 illustrates the blood ketone levelsafter administration of R-beta-hydroxybutyrate (5 g) and leucine (2 g).As illustrated, the administration of R-beta-hydroxybutyrate and leucinecauses greater elevation of blood ketone levels than the administrationof R-beta-hydroxybutyrate (5 g). The administration ofR-beta-hydroxybutyrate and leucine causes greater elevation of bloodketone levels than merely the additive effect of similar quantities ofR-beta-hydroxybutyrate and leucine administered separately.

End of Examples

In some implementations, one or more additives may be included in thecomposition, such as flavorings (e.g., natural and/or artificial),vitamins, minerals, binders, and/or any other appropriate additive.

The described compositions may be administered via any appropriateadministration method. For example, the described compositions may beadministered enterally and/or parenterally. In some implementations, thedescribed composition may be administered via a tablet and/or capsule.The described composition may be provided in a powdered form that allowsthe described composition to be sprinkled on food, mixed with a liquidto provide a beverage, and/or directly administered. The describedcomposition may be provided in gel form. The compounds in thecomposition may be mixed, coupled to each other, and/or providedseparately. For example, the composition may includebeta-hydroxybutyrate coupled to another compound (e.g.,beta-hydroxybutyrate ester and/or amino acid). In some implementations,the beta-hydroxybutyrate and one or more other compounds may be providedseparately (e.g., in pills). An individual may sequentially and/orconcurrently be administered (e.g., swallow pills) thebeta-hydroxybutyrate and other compounds.

The described compositions may be administered on an administrationprotocol to cause weight loss and/or maintain a weight of an individual;elevate and/or maintain blood ketone levels; increase and/or maintainketosis; and/or improve glucose tolerance (e.g., fasting glucose levelsmay be reduced and/or glucose metabolism may be improved), in someimplementations. For example, the described compositions may beadministered once a day, via an extended release preparation, and/ormultiple times a day (e.g., 1 to 5 times a day, 2 to 5 times a day, 3 to5 times a day, etc.). The described composition may replace otherpharmaceuticals or dietary supplements taken to promote weight loss,maintain a weight, promote ketosis, elevate blood ketone levels and/orbe utilized in combination with one or more other pharmaceuticals ordietary supplements, as appropriate. The described composition mayreplace other pharmaceuticals or dietary supplements taken for improvingglucose tolerance, such as metaformin, and/or be utilized in combinationwith one or more other pharmaceuticals or dietary supplements, asappropriate, in some implementations.

In various implementations, the described composition(s) (e.g.,butyrate, beta-hydroxybutyrate, R-beta-hydroxybutyrate, relatedcompounds, and/or one or more other compounds) may include one or moreof the described components, equivalent(s) of the describedcomponent(s), derivatives of the described component(s), complex(es) ofthe described component(s), salt(s) of the described component(s),and/or combinations thereof.

In various implementations, a pharmaceutically effective amount of oneor more of the described composition(s) may be administered.Administration of the pharmaceutically effective amount may induceand/or maintaining ketosis; maintaining and/or promoting weight loss;increase mental processes (e.g., acuity including cognitive functioning,mood, energy, alertness, focus, performance, effects of aging, etc.);improve and/or maintain body composition; function as a therapeutic forone or more of the described conditions or disorders (e.g., treatneurological disorders); and/or combinations thereof.

Although various types of increases in mental acuity have beendescribed, other features of mental acuity such as memory, focus,concentration, and/or understanding (e.g., speed of processing, accuracyof processing) may be increased by administration of an effective amountof the composition that includes R-beta-hydroxybutyrate.

Although a subject and/or an individual have been described as a human,a subject and/or individual may be a person or a group of people.Although various described systems and processes have been described asa being administered in humans, the described systems and processes maybe administered to other mammals, such as rats, dogs, etc.

In various implementations, beta-hydroxybutyrate may administeredsimultaneously and/or sequentially with one or more other compounds(e.g., short chain, medium chain, and/or long chain fatty acids). Forexample, beta-hydroxybutyrate and/or one or more other compounds may bedelivered mixed in a powdered, liquid, gel, and/or other appropriateform. In some implementations, the beta-hydroxybutyrate and/or one ormore other compounds may be administered via pills, tablets, capsules,other oral administration forms, intravenously, nasal sprays, sublingualtabs/strips, or topical delivery, rectal, other appropriateadministration forms, and/or combinations thereof.

Although the term beta-hydroxybutyrate is the terminology used in thedescribed implementations, beta-hydroxybutyrate is also referred to asbeta-hydroxybutyrate, (R)-3-Hydroxybutyric acid, (R)-3-Hydroxybutanoicacid, (3R)-3-hydroxybutanoic acid, (R)-3-Hydroxybutanoate,(R)-(−)-3-Hydroxybutyric acid, (R)-(−)-beta-Hydroxybutyric acid,3-D-hydroxybutyrate, BHIB, BHB, 3-delta-hydroxybutyrate,delta-3-hydroxybutyrate, 3-D-hydroxybutyric acid, D-3-hydroxybutyricacid, 3R-hydroxy-butanoic acid, delta-beta-hydroxybutyrate,D-3-hydroxybutyrate, D-(−)-3-hydroxybutyrate, delta-3-hydroxybutyricacid, (−)-3-Hydroxybutyric acid, D-beta-hydroxybutyrate,(R)-(−)-b-Hydroxybutyrate, (R)-beta-Hydroxybutyric acid,delta-(−)-3-hydroxybutyrate, (R)-3-hydroxybutyrate,(R)-beta-Hydroxybutanoic acid, (R)-(−)-beta-hydroxybutyrate,(−)-3-Hydroxy-n-butyric acid, (R)-(−)-b-Hydroxybutyric acid, Butanoicacid, 3-hydroxy-, (R)-Butyric acid, 3-hydroxy-, D-(−)—(R)-3-82578-46-9,beta-D-Hydroxybutyric acid, D-beta-Hydroxybutyric acid,(3R)-3-delta-hydroxybutyric acid, 3-(R)-Hydroxybutyric acid, and/or(−)-beta-Hydroxybutyrate.

In various implementations, beta-hydroxybutyrate is described asincluded in a composition; administered in an amount, form, and/orschedule; and/or being in a particular form (e.g., complexed and/orcoupled). R-beta-hydroxybutyrate may be utilized in the variousdescribed implementations of beta-hydroxybutyrate in the same or loweramount as the described beta-hydroxybutyrate, as appropriate.

It is to be understood the implementations are not limited to particularsystems or processes described which may, of course, vary. It is also tobe understood that the terminology used herein is for the purpose ofdescribing particular implementations only, and is not intended to belimiting. As used in this specification, the singular forms “a”, “an”and “the” include plural referents unless the content clearly indicatesotherwise. Thus, for example, reference to “a compound” includes acombination of two or more compounds and reference to “abeta-hydroxybutyrate” includes different types and/or combinations ofbeta-hydroxybutyrate.

Although the present disclosure has been described in detail, it shouldbe understood that various changes, substitutions and alterations may bemade herein without departing from the spirit and scope of thedisclosure as defined by the appended claims. Moreover, the scope of thepresent application is not intended to be limited to the particularembodiments of the process, machine, manufacture, composition of matter,means, methods and steps described in the specification. As one ofordinary skill in the art will readily appreciate from the disclosure,processes, machines, manufacture, compositions of matter, means,methods, or steps, presently existing or later to be developed thatperform substantially the same function or achieve substantially thesame result as the corresponding embodiments described herein may beutilized according to the present disclosure. Accordingly, the appendedclaims are intended to include within their scope such processes,machines, manufacture, compositions of matter, means, methods, or steps.

The invention claimed is:
 1. A method for maintaining or increasingweight loss in an individual, the method comprising: orallyadministering a composition, wherein the composition consisting of:approximately 0.5 g to approximately 10 g of R-beta-hydroxybutyrate,wherein the R-beta-hydroxybutyrate comprises one or more salts ofR-beta-hydroxybutyrate salt; at least one amino acid; and optionally, ofat least one of a flavoring, a vitamin, a mineral, or a binder; whereinadministration induces or maintains ketosis in an individual.
 2. Themethod of claim 1 wherein the amount of R-beta-hydroxybutyrate saltcomprises approximately 0.5 to approximately 3 g ofR-beta-hydroxybutyrate salt.
 3. The method of claim 1 wherein at leastone of the amino acids in the composition comprises leucine.
 4. Themethod of claim 1 wherein at least one of the amino acids in thecomposition comprises leucine, and wherein the amount of leucine in thecomposition comprises approximately 0.5 to approximately 2 g leucine. 5.The method of claim 1 wherein at least one of the amino acids in thecomposition comprises leucine, and wherein the amount of leucine in thecomposition comprises approximately 1 to approximately 3 g leucine. 6.The method of claim 1 wherein at least one of the amino acids and aportion of the R-beta-hydroxybutyrate of the composition are anR-beta-hydroxybutyrate-amino acid complex.
 7. The method of claim 1wherein administration of the composition increases mental acuity. 8.The method of claim 1 wherein the composition is administered up to 5times daily.
 9. The method of claim 1 wherein one or more of the saltsof R-beta-hydroxybutyrate salt comprise at least one of sodiumR-beta-hydroxybutyrate, potassium R-beta-hydroxybutyrate, magnesiumR-beta-hydroxybutyrate, or calcium R-beta-hydroxybutyrate salt.
 10. Themethod of claim 1 wherein administration of the composition increases atleast one of metabolism, fat loss, fat oxidation, motor function, ormuscle mass.
 11. A method for maintaining or inducing ketosis in anindividual, the method comprising: orally administering a composition,wherein the composition consisting of: 0.5 g to approximately 10 g ofR-beta-hydroxybutyrate, wherein the R-beta-hydroxybutyrate comprises oneor more salts of R-beta-hydroxybutyrate salt; and at least one aminoacid; and optionally, at least one of a flavoring, a vitamin, a mineral,or a binder; wherein administration induces or maintains ketosis in anindividual.
 12. The method of claim 11 wherein the amount ofR-beta-hydroxybutyrate salt comprises approximately 0.5 to approximately3 g of R-beta-hydroxybutyrate salt.
 13. The method of claim 11 whereinat least one of the amino acids in the composition comprises leucine.14. The method of claim 11 wherein at least one of the amino acids inthe composition comprises leucine, and wherein the amount of leucine inthe composition comprises approximately 0.5 to approximately 3 gleucine.
 15. The method of claim 11 wherein administration of thecomposition increases at least one of metabolism, fat loss, fatoxidation, motor function, or muscle mass.
 16. A method for maintainingketosis in an individual, the method comprising: orally administering acomposition, wherein the composition consisting of:beta-hydroxybutyrate, wherein the beta-hydroxybutyrate consistsessentially of: at least one polymer of beta-hydroxybutyrate; and 0.5 gto approximately 10 g of at least one salt of R-beta-hydroxybutyrate;and optionally at least one of a flavoring, a vitamin, a mineral, or abinder, wherein administration induces or maintains ketosis in anindividual.
 17. The method of claim 16 wherein the administration of thecomposition maintains or increases weight loss.
 18. The method of claim16 wherein the at least one of the R-beta-hydroxybutyrate saltscomprises at least one of sodium R-beta-hydroxybutyrate, potassiumR-beta-hydroxybutyrate, calcium R-beta-hydroxybutyrate, or magnesiumR-beta-hydroxybutyrate.
 19. The method of claim 16 whereinadministration of the composition increases at least one of metabolism,fat loss, fat oxidation, motor function, or muscle mass.
 20. The methodof claim 16 wherein administration of the composition increases mentalacuity.